Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1alpha and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses. In vivo, neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findings indicate that chemokines and their receptors have a critical role in determining the metastatic destination of tumour cells.

During the last five years, the development of bioinformatics and EST databases has been primarily responsible for the identification of many new chemokines and chemokine receptors. The chemokine field has also received considerable attention since chemokine receptors were found to act as co-receptors for HIV infection (1). In addition, chemokines, along with adhesion molecules, are crucial during inflammatory responses for a timely recruitment of specific leukocyte subpopulations to sites of tissue damage. However, chemokines and their receptors are also important in dendritic cell maturation (2), B (3), and T (4) cell development, Th1 and Th2 responses, infections, angiogenesis, and tumor growth as well as metastasis (5). Furthermore, an increase in the number of chemokine/receptor transgenic and knock-out mice has helped to define the functions of chemokines in vivo. In this review we discuss some of the chemokines' biological effects in vivo and in vitro, described in the last few years, and the implications of these findings when considering chemokine receptors as therapeutic targets.

Chemokines direct the trafficking of white blood cells in immune surveillance, playing a key role in inflammatory and infectious diseases such as AIDS. All chemokines studied so far are secreted proteins of relative molecular mass approximately 7K-15K and fall into three families that are defined by a cysteine signature motif: CXC, CC and C (refs 3, 6, 7), where C is a cysteine and X any amino-acid residue. We report here the identification and characterization of a fourth human chemokine type, derived from non-haemopoietic cells and bearing a new CX3C fingerprint. Unlike other chemokine types, the polypeptide chain of the human CX3C chemokine is predicted to be part of a 373-amino-acid protein that carries the chemokine domain on top of an extended mucin-like stalk. This molecule can exist in two forms: either membrane-anchored or as a shed 95K glycoprotein. The soluble CX3C chemokine has potent chemoattractant activity for T cells and monocytes, and the cell-surface-bound protein, which is induced on activated primary endothelial cells, promotes strong adhesion of those leukocytes. The structure, biochemical features, tissue distribution and chromosomal localization of CX3C chemokine all indicate that it represents a unique class of chemokine that may constitute part of the molecular control of leukocyte traffic at the endothelium.

DCs (dendritic cells) function as sentinels of the immune system. They traffic from the blood to the tissues where, while immature, they capture antigens. They then leave the tissues and move to the draining lymphoid organs where, converted into mature DC, they prime naive T cells. This suggestive link between DC traffic pattern and functions led us to investigate the chemokine responsiveness of DCs during their development and maturation. DCs were differentiated either from CD34+ hematopoietic progenitor cells (HPCs) cultured with granulocyte/macrophage colony–stimulating factor (GM-CSF) plus tumor necrosis factor (TNF)-α or from monocytes cultured with GM-CSF plus interleukin 4. Immature DCs derived from CD34+ HPCs migrate most vigorously in response to macrophage inflammatory protein (MIP)-3α, but also to MIP-1α and RANTES (regulated on activation, normal T cell expressed and secreted). Upon maturation, induced by either TNF-α, lipopolysaccharide, or CD40L, DCs lose their response to these three chemokines when they acquire a sustained responsiveness to a single other chemokine, MIP-3β. CC chemokine receptor (CCR)6 and CCR7 are the only known receptors for MIP-3α and MIP-3β, respectively. The observation that CCR6 mRNA expression decreases progressively as DCs mature, whereas CCR7 mRNA expression is sharply upregulated, provides a likely explanation for the changes in chemokine responsiveness. Similarly, MIP-3β responsiveness and CCR7 expression are induced upon maturation of monocyte- derived DCs. Furthermore, the chemotactic response to MIP-3β is also acquired by CD11c+ DCs isolated from blood after spontaneous maturation. Finally, detection by in situ hybridization of MIP-3α mRNA only within inflamed epithelial crypts of tonsils, and of MIP-3β mRNA specifically in T cell–rich areas, suggests a role for MIP-3α/CCR6 in recruitment of immature DCs at site of injury and for MIP-3β/CCR7 in accumulation of antigen-loaded mature DCs in T cell–rich areas.

The chemokine superfamily consists of a large number of ligands and receptors. At first glance, this family appears redundant and their ligand-receptor relationships promiscuous, making its study challenging. However, analyzing this family from the evolutionary perspective greatly simplifies understanding both the organization and function of this apparently complex system. In particular, the functions of a subgroup of chemokines (designated homeostatic chemokines) have played pivotal roles in advancing our understanding of the organization and function of the cellular networks that shape the immune system. Here, we update the full scope of the human and mouse chemokine superfamilies, their relationships, and summarize several important roles that homeostatic chemokines play in the immune system.